PROJECT SUMMARY Age is the main risk factor for Alzheimer's disease (AD), a neurodegenerative disorder rapidly increasing in both incidence and prevalence as the population becomes older. Unfortunately, AD is the only top ten cause of death with no effective treatments. Therefore, the development of disease-altering treatments for AD is an urgent and unmet need. Although the exact etiology of AD is unknown, microglia, the tissue-resident macrophages of the brain, have been implicated in disease pathogenesis based on the observation that genetic variants in several microglia-specific genes significantly alter disease risk. In the healthy brain, microglia maintain homeostasis through multiple modalities including phagocytic clearance of pathogens, apoptotic cells, and debris. In aging and AD brains, microglia are dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired homeostatic function. These findings suggest that the general decline in microglial function with age might underlie pathological neurodegeneration. However, the mechanisms of age-related microglial dysfunction are poorly understood. This proposal aims to elucidate the mechanisms of impaired microglial homeostasis in the aging brain and to uncover therapeutic strategies to reverse this impairment in AD. Our preliminary data suggest that CD22, a sialic-acid binding immunoglobulin-like lectin typically expressed on B-cells, inhibits phagocytosis in aged microglia and serves as a dominant regulator of microglial homeostasis. Aim 1 combines biochemical and genetic tools to identify upstream and downstream signaling partners that cooperate with CD22 to inhibit phagocytosis in microglia. Aim 2 will elucidate the role and regulation of microglial CD22 expression during development, aging, and AD. Aim 3 will define the neuronal response to restoration of microglial homeostasis upon CD22 blockade. Finally, Aim 4 will evaluate the therapeutic potential of blocking CD22 to ameliorate cognitive decline in mouse models of AD. These experiments will uncover a novel mechanism of microglial dysfunction during normal aging with direct translational implications for patients with AD.